Table 1.

Molecular systems and simulation protocols

	TIES	TIES‐λ‐REST (‐MBAR)	FEP+
Molecular systems	BRD4 (12 ligand pairs); MCL1 (16 ligand pairs); TYK2 (11 ligand pairs)
Force field	Amber ff99SBildn		OPLS3e
MD engine	NAMD 2.9	NAMD 2.11a	Desmond v3.8.5.19
Topology	Dual topology		Single topology
Box buffer [Å]	14		10
Timestep [fs]	2		4/8
Cut‐off [Å]	12		9
λ windows	13		12
Protocol	5 replicas, 4 ns production run for each λ window
Extensionb	–	4 ns, 20 replicas	4 ns, 30 replicas
		40 ns, 10 replicas	40 ns, 20 replicas
Hours/nsc	1.41d	2.36e	0.05f

^aCustomized version of the NAMD 2.11 package with a patch to implement the REST algorithm for alchemical simulations;

^b5 ligand pairs are chosen for each protein system;

^cuse TYK2 as an example;

^d128 cores on SuperMUC for one λ window;

^e124 cores on BlueWaters for one λ window;

^f4x Nvidia Tesla K80.